Download Series ‘‘CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION’’

Eur Respir J 2013; 41: 224–232
DOI: 10.1183/09031936.00047712
CopyrightßERS 2013
Series ‘‘CHRONIC THROMBOEMBOLIC PULMONARY
HYPERTENSION’’
Edited by J. Pepke-Zaba, M.M. Hoeper and M. Humbert
Number 1 in this Series
Vascular and right ventricular remodelling in
chronic thromboembolic pulmonary
hypertension
Marion Delcroix*, Anton Vonk Noordegraaf#, Elie Fadel", Irene Lang+,
Gérald Simonneau1 and Robert Naeijee
ABSTRACT: In chronic thromboembolic pulmonary hypertension (CTEPH) increased pulmonary
vascular resistance is caused by fibrotic organisation of unresolved thromboemboli. CTEPH
mainly differs from pulmonary arterial hypertension (PAH) by the proximal location of pulmonary
artery obliteration, although distal arteriopathy can be observed as a consequence of nonoccluded area over-perfusion. Accordingly, there is proportionally more wave reflection in
CTEPH, impacting on pressure and flow wave morphology. However, the time constant, i.e.
resistance6compliance, is not different in CTEPH and PAH, indicating only trivial effects of
proximal wave reflection on hydraulic right ventricular load. More discriminative is the analysis
of the pressure decay after pulmonary arterial occlusion, which is more rapid in the absence of
significant distal arteriopathy.
Structure and function of the right ventricle show a similar pattern to right ventricular
hypertrophy, namely dilatation and wall thickening, as well as loss of function in CTEPH and PAH.
This is probably related to similar loading conditions. Hyperventilation with hypocapnia is
characteristic of both PAH and CTEPH. Ventilatory equivalents for carbon dioxide, as a function of
arterial carbon dioxide tension, conform to the alveolar ventilation equation in both conditions,
indicating a predominant role of increased chemosensitivity. However, a slight increase in the
arterial to end-tidal carbon dioxide tension gradient in CTEPH shows a contribution of increased
dead space ventilation.
KEYWORDS: Chronic thromboembolic pulmonary hypertension, gas exchange, pulmonary
arterial hypertension, pulmonary circulation, remodelling, right ventricular function
hronic thromboembolic pulmonary hypertension (CTEPH) is characterised by the
presence of unresolved thromboemboli
undergoing fibrotic organisation. This results in
obstruction of proximal pulmonary arteries, increased pulmonary vascular resistance (PVR), pulmonary hypertension (PH) and progressive right
ventricle remodelling and failure. Pulmonary
embolism, either as single or recurrent episodes,
is thought to be the initiating event followed
by progressive pulmonary vascular remodelling.
CTEPH mainly differs from pulmonary arterial
hypertension (PAH) by the proximal location of
C
For editorial comments see page 8.
224
VOLUME 41 NUMBER 1
pulmonary artery obliteration, although distal
arteriopathy can be observed as a consequence of
non-occluded area over-perfusion [1]. Also characteristic for CTEPH is the extensive collateral
blood supply to the ischemic lung, developed from
the systemic circulation.
Diagnosis is based on the presence of pre-capillary
PH, defined by a mean pulmonary arterial
pressure (PAP) o25 mmHg and a wedge pressure
f15 mmHg, in combination with a lung scan
showing segmental perfusion defects after a
prolonged period of anticoagulation [2]. Further
AFFILIATIONS
*Dept of Pneumology, University
Hospitals of Leuven, Leuven, and
e
Dept of Physiology, Université Libre
de Bruxelles, Brussels, Belgium.
#
Dept of Pulmonary Diseases, VU
University Medical Center,
Amsterdam, The Netherlands.
"
Dept of Thoracic and Vascular
Surgery and Heart–Lung
Transplantation, Hôpital MarieLannelongue, Paris-Sud University,
Le Plessis Robinson, and
1
Centre National de Référence de
l’Hypertension Artérielle Pulmonaire,
Paris-Sud Université, Paris, France.
+
Dept of Internal Medicine II, Division
of Cardiology, Vienna General
Hospital, Medical University of
Vienna, Vienna, Austria.
CORRESPONDENCE
M. Delcroix
Dept of Pneumology, UZ Leuven,
Herestraat 49, 3000 Leuven
Belgium
E-mail [email protected]
Received:
March 19 2012
Accepted after revision:
April 27 2012
First published online:
Aug 16 2012
European Respiratory Journal
Print ISSN 0903-1936
Online ISSN 1399-3003
EUROPEAN RESPIRATORY JOURNAL
M. DELCROIX ET AL.
SERIES: CTEPH
evaluation is performed by helical computed tomography and
pulmonary angiography in order to localise vascular obstructions precisely.
is in keeping with previous observations in piglets with highflow PH induced by chronic aorto-pulmonary shunting [11, 12].
Pulmonary endarterectomy (PEA) is the treatment of choice for
CTEPH [3]. Under optimal conditions, including experienced
centres and selected patients, PEA can be performed with low
perioperative mortality, with improvements in haemodynamics, symptoms and survival [4]. However, only part of
the patients fulfil the criteria for surgical intervention and
some operated patients may experience a gradual haemodynamic and symptomatic decline related to secondary hypertensive arteriopathy in the small pre-capillary pulmonary
vessels [3]. Therefore, techniques to discriminate between
proximal and distal increases in PVR would be useful.
PULMONARY VASCULAR REMODELLING
Studies that describe the composition of the material removed
during PEA observed similarities with atherosclerotic lesions.
ARBUSTINI et al. [13] described two types of intimal lesions in PEA
material: 1) fibrous plaques with angiogenesis, and 2) atherosclerotic plaques that consist of cholesterol clefts, macrophages,
T-lymphocytes and calcification. A clinicopathological study
performed on 200 endarterectomised cases evidenced various
stages of thrombus remodelling, associated with variable degrees
of inflammation and cellularity within the specimen [14].
BLAUWET et al. [15] described organised thrombus formation
and intimal thickening consisting of collagen, inflammation,
calcification and atherosclerosis. The basic mechanisms responsible for this remodelling of proximal vessels will be described in
the next article in the series by LANG et al. [16].
MOSER et al. [7] described a chronic model of CTEPH in dogs by
combining embolisation of autologous blood thrombi with the
injection of tranexamic acid, a strong inhibitor of the fibrinolytic
system, or with addition of plasminogen activator inhibitor
type-1 [8]. Despite these attempts to stabilise thrombus, rapid
resolution occurred. More recently, FADEL et al. [9] used
unilateral pulmonary artery banding to mimic CTEPH in pigs.
However, this model could only answer questions on chronic
lung ischaemia, post-obstructive vasculopathy and reperfusion
injury, because it did not reproduce distal vascular remodelling
in the non-obstructed pulmonary arterial bed. Ligation of the
right or left pulmonary artery is not sufficient to cause PH, and
more extended ligation is lethal. Therefore, the same authors
later combined the ligation of the left pulmonary artery, via
sternotomy, with a weekly embolisation, under fluoroscopic
control, of tissue adhesive enbucrilate (Histoacryl1; Aesculap
AG, Tüttlingen, Germany) into the right lower lobe for 5 weeks
[10]. Thus, the right upper lobe arteries remained patent
reproducing the non-obstructed territories in CTEPH. This
progressive obstruction of the pulmonary arterial tree was
associated with sustained increase in mean PAP reaching or
exceeding 20 mmHg at 5 weeks. This piglet model of CTEPH
reproduced all aspects of the disease: increased PVR; increased
media thickness of distal pulmonary arteries in both obstructed
and non-obstructed lung areas; right ventricular hypertrophy;
increased tricuspid annular plane systolic excursion; and
paradoxical septal motion. The authors even observed increased
systemic blood supply through the bronchial arteries in the
obstructed areas. Interestingly, although the embolisations
were stopped after 5 weeks, the increase in PVR persisted for
up to 1 month later. An over-expression of endothelin-1 and
angiopoietin-1 was shown to occur in remodelled distal
arterioles of the unobstructed over-perfused lung areas, which
EUROPEAN RESPIRATORY JOURNAL
Distal pulmonary vascular remodelling is also involved in
the development of CTEPH. This is supported by the fact that:
1) there is a lack of correlation between elevated PAP and the
degree of angiographic pulmonary vascular bed obstruction;
2) PH progresses in the absence of recurrent embolism; and
3) PVR is still significantly higher in CTEPH patients than in
acute pulmonary embolism patients with a similar percentage
of vascular bed obstruction (fig. 1) [17–19].
In patients with concomitant small vessel arteriopathy, PH can
persist after PEA despite removal of proximal material, and is
associated with increased morbidity and mortality. More than
one-third of perioperative deaths and nearly half of long-term
deaths have been attributed to persistent PH [18, 20]. More
recently, persistent PH has been shown in 17% of a registry
population of 384 operated patients [4]. The current standard
40
TPR mmHg·L-1·min-1·m-2
ANIMAL MODELS OF CTEPH
In order to better understand the pathophysiology of the
disease, efforts have been taken to develop an animal model of
CTEPH. Acute pulmonary embolism can be reproduced in
different animal species, either with glass beads or autologous
blood clots. The development of a chronic model of CTEPH is
more challenging because of the very efficient endogenous
fibrinolytic system [5]. The systemic vascular response to
chronic pulmonary vascular obstruction also varies from
species to species, with proliferation of bronchial arteries into
the intraparenchymal airways in large animals or of intercostal
arteries into the pleural space in mice [6].
30
20
10
0
0
FIGURE 1.
20
40
60
80
Pulmonary vascular obstruction %
100
Relationship between pulmonary vascular obstruction score,
assessed by perfusion lung scan, and total pulmonary resistance (TPR) in acute
pulmonary embolism (open circles) and chronic thromboembolic pulmonary
hypertension (closed circles; CTEPH). For a given degree of obstruction, patients
with CTEPH had higher TPR values than patients with acute pulmonary embolism.
Reproduced from [17] with permission from the publisher.
VOLUME 41 NUMBER 1
225
c
SERIES: CTEPH
M. DELCROIX ET AL.
patients, if identified pre-operatively, could benefit from
medical therapy. However, PVR partitioning is technically
challenging requiring a perfect position of the Swan Ganz
catheter with regular pressure decay after occlusion, and has,
for a long time, not been further implemented and validated. A
recent study on a large number of patients seems to confirm
previous findings but also shows that discrimination on an
individual basis is insufficient for clinical decision [25].
pre-operative evaluation does not accurately detect the presence
or assess the degree of small vessel involvement in patients with
CTEPH, nor does it reliably predict post-operative haemodynamic outcome. The analysis of pressure decay curves after
pulmonary arterial occlusion (by the Swan Ganz catheter
balloon) was developed to estimate true pulmonary capillary
pressure and most probably approximates pre-capillary pressure
[21, 22]. Such curves consist of a first, fast component that
corresponds to the stop of flow through arterial resistance, and a
second, slower component, which corresponds to the emptying
of compliant capillaries through a venous resistance. From the
intersection of these two components, one calculates an
upstream resistance, essentially determined by the resistive
properties of the large pulmonary arteries, and the other a
downstream resistance, determined by the cumulated resistances of small arterioles, venules and capillaries [23]. KIM et al.
[24] showed a higher upstream resistance in patients with
CTEPH who had predominantly proximal (large-vessel) disease, whereas CTEPH patients with lower upstream resistance
had significant concomitant small-vessel disease and more
frequently persistent PH and death after PEA (fig. 2) [24]. These
a)
b)
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
Occlusion
Ppao
Poccl
0
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
1
2
3
4
5
6
7
8
9
10
Occlusion
Ppao
Poccl
0
FIGURE 2.
The bronchial vasculature is the systemic arterial blood supply
to the lung. Although small in relation to the pulmonary blood
flow, the bronchial vasculature serves important functions in
pulmonary vascular and airway diseases. Experimental lung
transplantation suggests that a loss of the bronchial artery supply
of airways may be a trigger of obliterative bronchiolitis [26].
However, systematic re-implantation of the bronchial arteries (i.e.
bronchial artery revascularisation) [27] has not resulted in the
prevention of bronchiolitis obliterans, or in an improved clinical
evolution including gas exchange or ventilatory responses.
However, recurrent haemoptysis has been successfully managed
by bronchial artery embolisation in PAH [28] and in CTEPH.
1
2
3
4
5
6
7
8
9
Pulmonary artery occlusion in two patients with a) primarily upstream resistance with a rapid drop in pressure to pulmonary arterial occlusion pressure (Ppao)
or ‘‘wedge’’, and b) significant downstream resistance with a longer time needed for the pressure to reach Ppao. Poccl: pulmonary capillary pressure after occlusion.
Reproduced from [24] with permission from the publisher.
226
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M. DELCROIX ET AL.
Increased wave reflection affects pulmonary pressure waves by
an increased pulse pressure, which is the difference between
systolic and diastolic pressure, and late systolic peaking of
pressure, because backward and forward waves add up to the
measured signal. For the flow, the backward wave is inversed
with respect to the forward wave, resulting in a late or midsystolic deceleration of the flow wave [40]. NAKAYAMA et al. [41]
measured pulse pressure relative to mean PAP (pulse pressure/
meanPAP 5 fractional pulse pressure) in 22 patients with CTEPH
and in 12 patients with idiopathic PAH. In patients with CTEPH,
fractional pulse pressure was 1.41¡0.2 compared to 0.80¡0.18 in
patients with idiopathic PAH [41]. This difference was highly
significant, and there was no overlap. The same authors repeated
the study in 19 patients with CTEPH and in 19 patients with
idiopathic PAH measuring systolic PAP (PAPsys) from the
maximum velocity of tricuspid regurgitation, and diastolic PAP
(PAPdias) from the maximum velocity of pulmonary regurgitation
[42]. While PAPsys was not different, fractional pulse pressure
was 1.65¡0.30 in the CTEPH patients and 0.94¡0.25 in the
idiopathic PAH patients. Receiver operating characteristics
analysis revealed that fractional pulse pressure separated
CTEPH from idiopathic PAH with a sensitivity of 0.95 and a
specificity of 1.0. NAKAYAMA et al. [43] went on to show the
relatively more important impact of wave reflection on PAP wave
morphology in CTEPH compared to idiopathic PAH. CTEPH
pressure waves presented with shorter time to inflection, and
increased difference between PAPsys and inflection pressure,
leading to an increased augmentation index calculated as
(PAPsys–inflection pressure)/pulse pressure. The authors found
that the augmentation index and the time to inflection discriminated 32 patients with CTEPH from 31 patients with idiopathic
PAH. However, this result was not confirmed by CASTELAIN et al.
Augmentation
index
130
PAPsys
=ΔP/PAPP
ΔP
PAPP
In contrast to the pulmonary circulation, the bronchial circulation has a remarkable ability to proliferate [36]. Numerous
reports have documented hypertrophy and angiogenesis of the
bronchial circulation in response to a variety of stimuli,
including chronic lung infections, pulmonary artery occlusion,
lung tumours and lung transplantation. Occlusion of one main
pulmonary artery stimulates angiogenesis in the bronchial
circulatory system of the ipsilateral lung [37]. Bronchial arteries
begin to enlarge as soon as 2–3 days after ligation of the
pulmonary artery and 50–200 mm pre-capillary anastomoses
form between the bronchial circulation and the pulmonary
artery. These anastomoses may maintain oxygenation of airway
epithelium and prevent epithelial–mesenchymal transition and
fibrosis [38], and may salvage the blood supply distal to the
complete occlusion of a pulmonary artery. Consequently, it has
been speculated that the ipsilateral bronchial artery blood
supply must be interrupted to maintain pulmonary artery
functional patency after unilateral surgical pulmonary endarterectomy. However, because bronchial walls do not allow
sufficient diffusion of carbon dioxide and oxygen, the role of the
bronchial circulation in maintaining gas exchange within the
lung distal to obstructed pulmonary arteries is doubtful.
Whether major vessel thrombus represents a stimulus for the
formation of bronchopulmonary anastomoses remains to be
determined. Few in-depth studies exist on the vascular biology
of the bronchial circulation. An increase in endothelial-1-like
immunoreactivity in newly formed bronchial arteries within the
ligated lung has been shown and suggests that endothelial-1,
among other angiogenic factors, for example hypoxia-inducible
factors-1 [39], may play a role in bronchial arterial angiogenesis
[19] and the integrity of airway microvasculature. Taken
together, much uncertainty still exists regarding the molecular
stimuli of collateral bronchial artery growth, and the precise role
of the bronchial circulation in CTEPH.
partial or complete occlusion of the proximal vessels leading to
pressure wave reflections. In addition, it was thought that the
involvement of the large vessels in the disease might decrease
compliance, out of proportion of increased resistance in these
patients.
Pressure mmHg
Normally, two-thirds of bronchial flow drains into the
pulmonary arteries and one-third into the pulmonary veins.
In contrast to patients with PAH, CTEPH patients may display
significant bronchopulmonary collateral blood flow, accounting for up to 30% of systemic blood flow draining directly into the
pulmonary veins [29, 30]. The presence of bronchial collaterals
has been used as a ‘‘biomarker’’ for the diagnosis of CTEPH [31].
A linear correlation exists between the magnitude of bronchosystemic shunt and dilatation of the bronchial arteries in patients
with CTEPH [32]. There is little evidence that acute bronchial
vascular congestion contributes significantly to airway narrowing. Post-operative PVR is lower in patients with dilated
bronchial arteries, and dilated bronchial arteries have been
positively correlated with a lower mortality rate after PEA [33].
A probable explanation for these observations is that a large
bronchial collateral circulation is commonly associated with
proximal occlusion (i.e. type 1 CTEPH, Jamieson classification
[34]) and operable disease. Current evidence is not sufficient to
support invasive bronchial artery angiography as a routine
method for the diagnosis and prognostic assessment of CTEPH
[35], but evaluation of the bronchial circulation on the helical
computed tomography images should be considered.
SERIES: CTEPH
PAPpi
PAPdias
20
ti
250 ms
Systolic time
Time
Heart period
FIGURE 3.
Typical pulmonary artery pressure (PAP) tracings. Chronic
thromboembolic pulmonary hypertension patients have an increased time to
PRESSURE AND FLOW WAVE MORPHOLOGY
It was believed that loading conditions in CTEPH are different
from other types of PH, based on the fact that CTEPH causes
diastolic PAP. Reproduced from [44] with permission from the publisher.
EUROPEAN RESPIRATORY JOURNAL
VOLUME 41 NUMBER 1
inflection (ti) and augmentation index. PAPP: pulmonary artery pulse pressure; DP:
change in pressure; PAPpi: PAP at the inflexion point; PAPsys: systolic PAP; PAPdias:
227
c
SERIES: CTEPH
M. DELCROIX ET AL.
[44] who performed PAP wave analysis with high-fidelity
micromanometer-tipped catheters in 14 patients with CTEPH
and seven patients with idiopathic PAH. Both groups had
comparable cardiac index, mean PAP, pulse pressure and
fractional pulse pressure. The time to inflection and the
augmentation index were increased in CTEPH patients (fig. 3),
but the measurements did not allow for sufficient discrimination.
PAPsys and PAPdias in CTEPH are proportional to the mean in
a similar way as in idiopathic PAH [45]. Proportionality of the
PAPsys and PAPdias can only be explained if the time constant,
which is the product of resistance and compliance, is constant at
Notch ratio
t1/t2
a)
t1
the same value in CTEPH and idiopathic PAH [46]. Indeed,
several studies have confirmed that the load of the right
ventricle, described by resistance 6 compliance product, is
similar for CTEPH and idiopathic PAH [47–49]. For example,
LANKHAAR et al. [46] showed that in patients with CTEPH
(n510), idiopathic PAH (n59) and controls without PH (n510),
the time constant was always equal to 0.72 s. The explanation for
this is that compliance and resistance are equally distributed
over the pulmonary vascular bed. Indeed, SAOUTI et al. [50]
showed that only 30% of compliance is localised in the large
pulmonary artery vessels. Another strong supporting argument
is that the time constant remains unaffected by endarterectomy
t2
t1
Notch ratio <1
t2
Notch ratio >1
Pulmonary artery systolic flow
b)
FIGURE 4.
c)
d)
a) Notch ratio calculated on Doppler pulmonary flow waves. b–d) Pulmonary flow waves (top tracings) and tricuspid regurgitant jets (bottom tracings) in
different patients with chronic thromboembolic pulmonary hypertension. b) Exercise-induced pulmonary hypertension, and c, d) with similar severity of pulmonary
hypertension but a notch ration ,1 and .1, respectively. t1: time interval from the onset of pulmonary artery systolic flow to the maximal systolic flow deceleration; t2: time
interval from the maximal systolic flow deceleration to the end of pulmonary artery systolic flow. Reproduced from [52] with permission from the publisher.
228
VOLUME 41 NUMBER 1
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M. DELCROIX ET AL.
[49]. This similar relationship in CTEPH and PAH predicts that,
for a similar PVR, right ventricular load must be similar [50, 51].
A disproportionate increase in pulse pressure because of
haemodynamically significant wave reflection would have
decreased the time constant of the pulmonary circulation
because of a decreased compliance at any given PVR. These
results suggest that increased wave reflection in CTEPH does not
affect monotonous response of the pulmonary circulation to
vascular disease.
HARDZIYENKA et al. [52] reasoned that increased wave reflection in
CTEPH should affect Doppler pulmonary flow wave morphology by an increased late or mid-systolic deceleration (notching) of
flow. They defined a time to notching expressed as a notch ratio,
or the ratio of time from onset of flow to maximum flow
deceleration to time from maximum flow deceleration to end of
flow (fig. 4). A notch ratio .1 in 18 out of 58 consecutive patients
with CTEPH undergoing PEA was found to be associated with
in-hospital mortality and persistent post-operative PH. Thus an
increased notch ratio would allow for the identification of
peripheral small vessel disease that is not amenable to surgery,
as an early notch would indicate a proximal obstruction site while
a late notch maps the obstruction to a more distal location.
However, while this result is in keeping with predicted increased
effects of reflections on proximal obstruction in CTEPH [53], the
method has not been evaluated prospectively in larger patient
populations. It would be interesting to combine pressure- and
flow-wave analysis, which has not yet been attempted. A recent
study revisited simple visual assessment of pulmonary flow
wave morphology for the diagnosis of PH [54]. In 88 patients
referred for PH and 32 patients with systolic heart failure, midsystolic or late-systolic notching was highly associated with an
increased PVR .3 Wood Units, whereas a normal shape of the
pulmonary flow wave predicted a PVR ,3 Wood Units. Because
of increased wave speed along with severity of PH, pressure and
wave morphology changes may also occur in pulmonary
vascular disease with a purely distal site of increased PVR [53].
RIGHT VENTRICULAR REMODELLING
Right heart failure is caused by exposure to pressure overload
of the right ventricle. Similar loading conditions in CTEPH and
other types of PH have been discussed previously. Patient
outcome is predominantly determined by the response of the
right ventricle to this increased load [55]. Initially, the increase
in pressure leads to an increase in wall stress causing an
augmentation of wall thickness by increasing the muscle mass
resulting in right ventricle hypertrophy. This increase in
ventricular mass is predominantly the result of protein
synthesis and an increase in cell size through the addition of
sarcomeres. However, the right ventricle is not capable of
sustaining a long-term pressure overload. Eventually, cardiac
contractile force decreases resulting in right ventricular
dilation. This dilation increases the wall tension which requires
a higher oxygen demand and decreases the perfusion leading
to a vicious circle of further compromised contractility and
dilation [56]. Maladaptive neurohumoral signalling, oxidative
stress and inflammatory responses may further accelerate the
development of right heart failure, characterised by increasing
filling pressures, diastolic dysfunction and diminished cardiac
output. Pressure overload and right ventricular hypertrophy
might also result in diastolic dysfunction of the left ventricle
EUROPEAN RESPIRATORY JOURNAL
SERIES: CTEPH
through ventricular interdependence and leftward septal
displacement. The specific mechanisms underlying the transition from hypertrophy to dilation in right ventricular failure
secondary to PH remain unclear [55].
The period between the episode of acute embolism, if known
by the patient, and symptoms of CTEPH varies considerably
from patient to patient [1]. Since the right ventricle needs time to
adapt to the increased load, this variable time-course might
explain the differences in right heart function seen between
CTEPH patients. Some CTEPH patients only have mild
symptoms and a preserved right ventricular function at the time
of presentation despite having a high PVR, whereas others
present with overt right ventricular failure despite a low PVR.
This variation between patients in right ventricular adaptation
might be more prominent in the CTEPH patient group than in
PAH. Whether the right ventricular remodelling in CTEPH is, on
average, different from other types of PH is unknown. The age of
CTEPH patients at the time of presentation is, on average, higher
than in most PAH subgroups, which might limit the right
ventricle in its ability to remodel. Comparing magnetic resonance
imaging data of the right ventricle of 17 CTEPH patients with
operable disease showed identical data for PAP, stroke volume,
right ventricular ejection fraction and mass than a cohort of 64
patients with idiopathic PAH reported by the same group [57,
58]. Another way to look for possible differences between right
ventricular adaptation in CTEPH versus other types of PAH is to
compare haemodynamics. If PAP is lower for a given PVR in
CTEPH this provides evidence that right ventricular function is
more impaired in CTEPH. To date, no studies have been
specifically designed to investigate this question. Reported
haemodynamic data from a study by QUARCK et al. [59] showed
that PAP was, on average, lower in the CTEPH group than PAH
(table 1). However, PVR was also lower in CTEPH in this study,
although not significant. Comparing the haemodynamic data of
randomised controlled trials performed exclusively in CTEPH,
the BENEFIT trial [60], or solely in PAH, the BREATHE-1 study
[61], a similar pattern was observed although PVR was, on
average, different between both studies (table 1). However, there
was a significant age difference between both studies. Thus,
although reported haemodynamic data might suggest that right
TABLE 1
Demographic and pulmonary haemodynamic
parameters in patients with pulmonary arterial
hypertension (PAH) and chronic thromboembolic
pulmonary hypertension (CTEPH)
Subjects n
Age yrs
Females
PAP mmHg
PAH
CTEPH
BREATHE-1
BENEFIT
[59]
[59]
[61]
[60]
104
79
213
157
58¡15
62¡14*
48¡16
63¡11
66
62
79
65
50¡13
45¡11*
54¡16
46¡11
PVR dyn?s?cm-5
850¡397
804¡381
970¡630
702¡328
CI L?min-1?m-2
2.42¡0.81
2.19¡0.53*
2.4¡0.8
2.29¡0.55
Data are presented as mean¡
SD
or %, unless otherwise stated. PAP:
pulmonary artery pressure; PVR: pulmonary vascular resistance, CI: cardiac
index. *: p,0.05 versus PAH, only available for [59].
VOLUME 41 NUMBER 1
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M. DELCROIX ET AL.
After PEA the right ventricle function improves, together with
a reduction of right ventricular mass, size and strain [63]. PEA
normalises interventricular asynchrony and right ventricular
systolic wall stress. It has, however, been observed that this
recovery is not complete [57, 64, 65]. Right ventricular mass
measured by magnetic resonance imaging decreases significantly but does not completely normalise [57]. Moreover, the
tricuspid annular plane systolic excursion initially deteriorates
after PEA with an incomplete restoration after 1 yr of follow-up
[64], although this acute post-operative deterioration could be
explained by post-operative changes in global heart motion [66].
One explanation for these observations is recent evidence
that right ventricle loading conditions are not normalised in
CTEPH patients although PAP nearly normalised [48, 49]. After
successful PEA with persistent exertional dyspnoea, patients
display an abnormal pulmonary haemodynamic response to
exercise, characterised by increased PVR and decreased compliance, which is an independent predictor of limited exercise
capacity [48]. Thus, although intrinsic damage of the right
ventricle cannot be excluded, the most likely explanation for
persisting minimal structural and functional abnormalities of
the right ventricle is increased load.
VESSEL OBSTRUCTION AND DEAD SPACE
VENTILATION
Pulmonary gas exchange is determined by ventilation, perfusion and diffusion. Large vessel and cardiac remodelling are,
therefore, expected to influence gas exchange in CTEPH.
However, in spite of extensive vascular obstruction and
obliteration, pulmonary gas exchange is generally well
preserved in both PAH and CTEPH [67–72]. Patients with
both idiopathic PAH and CTEPH usually present with only
mild-to-moderate hypoxaemia, most often with hypocapnia,
and cannot actually be differentiated on the basis of arterial
blood gas analysis [67]. Measurements of ventilation/perfusion (V9/Q9) distributions using the multiple inert gas
elimination technique in both conditions generally show:
preserved matching of V9/Q9modes; a mild to moderately
increased perfusion to lung units with lower than normal
V9/Q9; no or minimal pulmonary shunting; and no diffusion
limitation [68–72]. The mean V9/Q9in both CTEPH and PAH is
shifted to higher V9/Q9in relation to hyperventilation, which
decreases the efficiency of gas exchange and increases
physiologic dead space [73]. Anatomic dead space, or inert
gas dead space defined by a V9/Q9 .100, remains normal or
near-normal, and V9/Q9distributions do not usually exhibit
higher than normal V9/Q9modes. When hypoxaemia occurs, it
is mostly due to a low mixed venous oxygen tension as a result
of low cardiac output at rest as well as at exercise, in the
context of right ventricular failure. In some patients, hypoxaemia is caused by right-to-left shunting through a patent
230
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foramen ovale [70]. Arterial hypocapnia is typically present in
both PAH and CTEPH. Hypocapnia in PAH has been shown to
be associated with a decreased survival [74].
Patients with either PAH or CTEPH hyperventilate at rest and
during exercise. Hyperventilation in both conditions cannot be
explained by arterial hypoxaemia. Hyperventilation causes the
Bohr physiological dead space calculation to increase, because of
disproportionate effects on arterial and mixed expired carbon
dioxide tension. Therefore, it is difficult to evaluate the respective
contributions of wasted ventilation and chemosensitivity to
increased ventilation in patients with idiopathic PAH and
CTEPH. This problem can be explored by plotting ventilatory
equivalents for carbon dioxide (minute ventilation (V’E)/carbon
dioxide production (V’CO2)) at exercise as a function of arterial
carbon dioxide tension (Pa,CO2) or end-tidal carbon dioxide
tension (PET,CO2) during exercise [75]. ZHAI et al. [76] recently
reported on these measurements in 50 patients with CTEPH and
77 patients with PAH. Physiological dead space at maximal
exercise and V’E/V’CO2 as a function of Pa,CO2 were increased in
CTEPH compared to PAH (fig. 5), but the difference disappeared
when V’E/V’CO2 was expressed as a function of PET,CO2; thus, it is
strongly suggestive of a contribution of increased dead space
ventilation in CTEPH. It is of interest that V’E/V’CO2 versus
PET,CO2 or Pa,CO2 in PAH patients conformed to the alveolar
ventilation equation, which, together with hypocapnia, shows the
major contribution of increased chemosensitivity in this condition. However, figure 5 shows a considerable overlap, so that
individual discrimination between CTEPH and PAH on the basis
of gas exchange and ventilatory measurements is not possible.
CONCLUSION
In CTEPH, vascular obstruction is originally proximal with
some distal remodelling as a consequence of prolonged overperfusion. Accordingly, there is proportionally more wave
reflection in CTEPH than in PAH, impacting on pressure and
120
CTEPH
PAH
100
Peak EqCO2
ventricular adaptation is less in CTEPH than PAH, it is unknown
whether these differences are explained by disease specific
factors or age. Pump function graphs (right ventricle pressure
versus stroke volume at steady state) or ventriculo-arterial
coupling measurements (right ventricle pressure versus volume
measurements over time) [62] in age-matched patients with both
forms of PH, would help to solve this question but require
invasive right ventricle pressure and volume tracings which are
currently unavailable.
80
60
40
20
0
2
FIGURE 5.
3
4
5
Pa,CO2 kPa
6
7
Ventilatory equivalent for CO2 (EqCO2) as a function of arterial
carbon dioxide tension (Pa,CO2) during exercise in patients with either chronic
thromboembolic pulmonary hypertension (CTEPH) or pulmonary arterial hypertension (PAH). Increased minute ventilation/carbon dioxide production at lower Pa,CO2
reflects increased chemosensitivity but Pa,CO2 is higher in CTEPH, indicating a
contribution of dead space to increased ventilation. Reproduced from [76] with
permission from the publisher.
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STATEMENT OF INTEREST
Statements of interest for M. Delcroix, A. Vonk-Noordegraaf, I. Lang,
G. Simonneau and R. Naeije can be found at www.erj.ersjournals.com/
site/misc/statements.xhtml
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